Stiripentol, sold under the brand name Diacomit, is an anticonvulsant medication used for the treatment of

Dravet syndrome Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or feve ...

- a serious genetic brain disorder. The most common side effects include loss of appetite, weight loss, insomnia (difficulty sleeping), drowsiness, ataxia (inability to co‑ordinate muscle movements), hypotonia (low muscle strength) and dystonia (muscle disorders).

Medical uses

In the European Union, stiripentol is

indicated In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...

for use in conjunction with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in people with severe myoclonic epilepsy in infancy (SMEI, Dravet's syndrome) whose seizures are not adequately controlled with clobazam and valproate. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. In the United States, stiripentol is indicated for the treatment of seizures associated with Dravet syndrome in people two years of age and older taking clobazam. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome. It is used in some countries as an add-on therapy with

sodium valproate Valproate (VPA) and its valproic acid, sodium valproate, and valproate semisodium forms are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those ...

and

clobazam Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselect ...

for treating children with

whose seizures are not adequately controlled. As of 2017, it was not known whether stiripentol remains useful as children become adolescents or adults.

Contraindications

Stiripentol must not be used in people who have had psychosis (a serious mental state with a distorted sense of reality) with attacks of delirium (a mental state with confusion, excitement, restlessness and hallucinations).

Adverse effects

Very common (more than 10% of people) adverse effects include loss of appetite, weight loss, insomnia, drowsiness,

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

hypotonia Hypotonia is a state of low muscle tone (the amount of tension or resistance to stretch in a muscle), often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases ...

, and dystonia. Common (between 1% and 10% of people) adverse effects include neutropenia (sometimes severe), aggressiveness, irritability, behavior disorders, opposing behavior, hyperexcitability, sleep disorders, hyperkinesias, nausea, vomiting, and elevated

gamma-glutamyltransferase Gamma-glutamyltransferase (also γ-glutamyltransferase, GGT, gamma-GT, gamma-glutamyl transpeptidase; ) is a transferase (a type of enzyme) that catalyzes the transfer of gamma-glutamyl functional groups from molecules such as glutathione to ...

Interactions

Stiripentol inhibits several

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

isoenzymes and so interacts with many anticonvulsants and other medicines.

Pharmacology

As with most anticonvulsants, the precise mechanism of action is unknown. Regardless, stiripentol has been shown to have anticonvulsant effects of its own. Stiripentol increases GABAergic activity. At clinically relevant concentrations, it enhances central GABA neurotransmission through a barbiturate-like effect, since it increases the duration of opening of GABA-A receptor channels in hippocampal slices. It has also been shown to increase GABA levels in brain tissues by interfering with its reuptake and

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...

. Specifically, it has been shown to inhibit

lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one ...

, which is an important enzyme involved in the energy metabolism of neurons. Inhibition of this enzyme can make neurons less prone to fire action potentials, likely through activation of ATP-sensitive potassium channels. Stiripentol also improves the effectiveness of many other anticonvulsants, possibly due to its inhibition of certain enzymes, slowing the drugs' metabolism and increasing

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

levels.

Chemistry

Stiripentol is an α-ethylene alcohol; its chemical formula is 4,4-dimethyl-1- ,4-(methylendioxy)-phenyl1penten-3-ol. It is chiral and used medically as the racemate. The R enantiomer appears to be around 2.5 times more active than the S enantiomer.

History

Stiripentol was discovered in 1978 by scientists at Biocodex and clinical trials started over the next few years. It was originally developed for adults with focal seizures, but failed a Phase III trial. In December 2001, the European Medicines Agency (EMA) granted stiripentol orphan drug status (designation number EU/3/01/071) for the treatment of

severe myoclonic epilepsy of infancy Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or feve ...

(SMEI, also known as Dravet's syndrome) in children and in January 2007, the EMA granted the drug a marketing authorisation for use of the drug as an add-on to other anti-seizure drugs. It was approved in Canada for this use in May 2013. As of 2017, it was also approved for this use in Japan. In August 2018, stiripentol was approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) as an adjunctive therapy for Dravet Syndrome.

Society and culture

Economics

Prior to approval in the US, parents of children with Dravet Syndrome were paying around $1,000 for a month supply to obtain it from Europe.

References

External links

* {{Portal bar , Medicine Secondary alcohols Anticonvulsants Orphan drugs Benzodioxoles Alkene derivatives GABAA receptor positive allosteric modulators Tert-butyl compounds